Zeng Sen, Yang Honglan, Wang Binghao, Xie Yongzhi, Xu Ke, Liu Lei, Cao Wanqian, Liu Xionghao, Tang Beisha, Liu Mujun, Zhang Ruxu
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
Neural Regen Res. 2024 Jan;19(1):205-211. doi: 10.4103/1673-5374.375347.
Mutations in the microrchidia CW-type zinc finger protein 2 (MORC2) gene are the causative agent of Charcot-Marie-Tooth disease type 2Z (CMT2Z), and the hotspot mutation p.S87L is associated with a more severe spinal muscular atrophy-like clinical phenotype. The aims of this study were to determine the mechanism of the severe phenotype caused by the MORC2 p.S87L mutation and to explore potential treatment strategies. Epithelial cells were isolated from urine samples from a spinal muscular atrophy (SMA)-like patient (MORC2 p.S87L), a CMT2Z patient (MORC2 p.Q400R), and a healthy control and induced to generate pluripotent stem cells, which were then differentiated into motor neuron precursor cells. Next-generation RNA sequencing followed by KEGG pathway enrichment analysis revealed that differentially expressed genes involved in the PI3K/Akt and MAPK/ERK signaling pathways were enriched in the p.S87L SMA-like patient group and were significantly downregulated in induced pluripotent stem cells. Reduced proliferation was observed in the induced pluripotent stem cells and motor neuron precursor cells derived from the p.S87L SMA-like patient group compared with the CMT2Z patient group and the healthy control. G0/G1 phase cell cycle arrest was observed in induced pluripotent stem cells derived from the p.S87L SMA-like patient. MORC2 p.S87L-specific antisense oligonucleotides (p.S87L-ASO-targeting) showed significant efficacy in improving cell proliferation and activating the PI3K/Akt and MAPK/ERK pathways in induced pluripotent stem cells. However, p.S87L-ASO-targeting did not rescue proliferation of motor neuron precursor cells. These findings suggest that downregulation of the PI3K/Akt and MAPK/ERK signaling pathways leading to reduced cell proliferation and G0/G1 phase cell cycle arrest in induced pluripotent stem cells might be the underlying mechanism of the severe p.S87L SMA-like phenotype. p.S87L-ASO-targeting treatment can alleviate disordered cell proliferation in the early stage of pluripotent stem cell induction.
微小睾丸 CW 型锌指蛋白 2（MORC2）基因突变是 2Z 型夏科 - 马里 - 图斯病（CMT2Z）的致病因素，热点突变 p.S87L 与更严重的脊髓性肌萎缩样临床表型相关。本研究的目的是确定 MORC2 p.S87L 突变导致严重表型的机制，并探索潜在的治疗策略。从一名脊髓性肌萎缩（SMA）样患者（MORC2 p.S87L）、一名 CMT2Z 患者（MORC2 p.Q400R）和一名健康对照的尿液样本中分离上皮细胞，并诱导生成多能干细胞，然后将其分化为运动神经元前体细胞。通过下一代 RNA 测序并进行 KEGG 通路富集分析发现，参与 PI3K/Akt 和 MAPK/ERK 信号通路的差异表达基因在 p.S87L SMA 样患者组中富集，并且在诱导多能干细胞中显著下调。与 CMT2Z 患者组和健康对照相比，p.S87L SMA 样患者组来源的诱导多能干细胞和运动神经元前体细胞的增殖减少。在 p.S87L SMA 样患者来源的诱导多能干细胞中观察到 G0/G1 期细胞周期停滞。MORC2 p.S87L 特异性反义寡核苷酸（靶向 p.S87L-ASO）在改善诱导多能干细胞的细胞增殖和激活 PI3K/Akt 和 MAPK/ERK 通路方面显示出显著效果。然而，靶向 p.S87L-ASO 并不能挽救运动神经元前体细胞的增殖。这些发现表明，PI3K/Akt 和 MAPK/ERK 信号通路的下调导致诱导多能干细胞中细胞增殖减少和 G0/G1 期细胞周期停滞，可能是严重 p.S87L SMA 样表型的潜在机制。靶向 p.S87L-ASO 治疗可以缓解多能干细胞诱导早期的细胞增殖紊乱。
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